Intraperitoneal treatment of bacterial peritonitis
New pharmaceutical composition for intraperitoneal treatment
Reponex Pharmaceuticals Ltd. has filed a patent application relating to a pharmaceutical composition for a novel method of treating bacterial peritonitis. The inventors are Professor Lars Heslet, MD, and Professor Lars Otto Uttenthal, DPhil. A clinical proof-of-concept study has been initiated.
The essential new features are:
1. Intraperitoneal administration
Post-surgical antibacterial treatment is carried by the intraperitoneal administration of the preparation, not the conventional systemic (e.g. intravenous) administration of antibiotics. The pharmaceutical composition is dissolved in saline or a physiological salt composition similar to peritoneal dialysis fluid. An intraperitoneal catheter placed as for peritoneal dialysis.
Advantage: This procedure achieves high local concentrations of the active substances where their effect is required, with lower systemic concentrations and reduced risk of systemic side effects. It is particularly important to administer GM-CSF intraperitoneally as systemic therapy has a weaker local effect with risk of major systemic side effects.
2. Double action to combat the bacterial infection
- Cytokinet GM-CSF (molgramostim: recombinant human GM-CSF expressed in E. coli) is given in a low intraperitoneal dose. This restores the often impaired function of the peritoneal macrophages and recruits additional macrophages into the peritoneum, with enhanced bacterial clearance via the innate defense mechanisms.
- Antibiotika given at high local concentrations. Fosfomycin is chosen because it is an antibiotic with an appropriate antibacterial spectrum, which also active against ESBL coliforms and MRSA, while it is non-toxic at the cellular and systemic level.
Selgas R et al (1996) Immunomodulation of peritoneal macrophages by granulocyte-macrophage colony-stimulating factor in humans. Kidney Int 50: 2070-2078. In peritoneal dialysis patients, the addition of GM-CSF to the dialysis fluid resulted in a pronounced transient recruitment of “primed” macrophages into the peritoneum without raising levels of markers of inflammation. It was concluded that GM-CSF may increase the peritoneal defense capability through enhancement of the effector functions of pre-existing and newly recruited macrophages. At the same time the study gives an indication of the dosage level that has the desired effect without producing side effects.
H Orozco et al (2006) Molgramostim (GM-CSF) associated with antibiotic treatment in nontraumatic abdominal sepsis: a randomized, double-blind, placebo-controlled clinical trial. Arch Surg 141: 150-153; discussion 154. In surgical patients with bacterial peritonitis, subcutaneous GM-CSF reduced the occurrence of infectious complications and the number of days of hospitalization.
There are studies reporting the successful treatment of bacterial peritonitis associated with peritoneal dialysis by giving intraperitoneal fosfomycin. In this type of peritonitis, however, the bacterial spectrum is different from that of peritonitis due to intestinal perforation, as staphylococci occur with greater frequency:
Michel C et al (1989) Treatment of peritonitis in continuous ambulatory peritoneal dialysis with a combination of fosfomycin and pefloxacin. Pathol Biol (Paris) 37: 269-271.
There is also an extremely useful study of the pharmacokinetics of intraperitoneal fosfomycin in peritoneal dialysis patients, which provide information that is relevant to dosage:
Tobudic S et al (2012) Pharmacokinetics of intraperitoneal and intravenous fosfomycin in automated peritoneal dialysis patients without peritonitis. Antimicrob Agents Chemother 56: 3992-3995.
The following is a review of current status and renewed use of fosfomycin:
Michalopoulos AS et al (2011) The revival of fosfomycin. Int J Infect Dis 15: e732-e739.